PROJECT SUMMARY/ABSTRACT Hemochorial placentation occurs in many mammalian species including primates and rodents. It ensures the most intimate contact between maternal and embryonic compartments and requires specialized adjustments. Among these adjustments is the need for extensive remodeling of the maternal uterine spiral arteries. Uterine vascular modifications are required for the delivery of nutrients to the fetus. Disruptions in this fundamental process lead to diseases of pregnancy and placentation, and result in impaired nutrient transport to the fetus, including the delivery of oxygen. Hypoxemia leads to a range of disruptive events within the fetus that have potentially long-lasting postnatal impacts on health and disease. Mechanisms controlling uterine spiral artery remodeling remain poorly understood. Central to the vascular remodeling process is a specialized population of trophoblast cells referred to as invasive trophoblast or alternatively as extravillous trophoblast. Regulatory processes controlling differentiation and function of the extravillous trophoblast cell lineage is the focus of this proposal. The rat is used as an experimental model in this investigation because it exhibits deep intrauterine trophoblast invasion and extensive uterine spiral artery remodeling. These events are remarkably similar to that observed in human placentation. The experimental effort is based on our prior establishment and extensive characterization of in vitro and in vivo models for studying rat hemochorial placentation. Through these efforts we discovered key regulators that promote development of the invasive trophoblast lineage: i) Fos like antigen 1/JunB protooncogene; ii) hypoxia/hypoxia inducible factor/lysine demethylase 3A/matrix metalloproteinase 12. These regulators contribute to establishing tissue plasticity and safeguard placental health. Most importantly, we have determined that plasticity is a hallmark of a healthy placenta. In this proposal we utilize FOS Like Antigen 1/JunB protooncogene and hypoxia/hypoxia inducible factor/ lysine demethylase 3A/matrix metalloproteinase 12 regulatory circuits as centerpieces and guides to mechanisms controlling the development of the extravillous trophoblast lineage. The proposed research provides an innovative approach to studying hemochorial placentation. Collectively, the research is directed toward elucidating molecular mechanisms underlying physiological processes that ensure appropriate hemochorial placentation. This approach will lead to the identification of conserved regulatory pathways controlling the extravillous trophoblast lineage, which will create opportunities for new scientific and applied pursuits.